Gao Lab

Overview

Research in the Gao Lab primarily involves the discovery, development and use of adeno-associated virus vectors for gene therapy of genetic diseases and the study of miRNA functions in mammals. The lab continues to work on isolation, characterization and vectorology of novel AAV vectors from primate tissues, molecular mechanisms of AAV evolution and diversity, and molecular interactions between endogenous AAV, AAV vector, host genomes and innate RNAi defense pathways. We also develop novel strategies for rAAV gene therapy of an inherited neurodegenerative disease, Canavan Disease, using novel AAVs that can cross the blood-brain-barrier for efficient CNS gene delivery and endogenous miRNA-mediated posttranscriptional de-targeting. Another area of research interest in the lab is to explore AAV vectors for delivery of denovo synthesized biological miRNA antagonists or over express microRNAs to elucidate micro RNA functions in adult mammals.

Current Research

1. AAV vector holds great promise for gene therapy application. Our lab previously isolated a diverse family of natural variants of primate AAVs some of which have unique tissue tropism and can accomplish highly efficient and stable gene transfer. We are currently expanding the novel AAV discovery effort to chimpanzee tissues, considering its phylogenetic closeness to humans. We focus our effort on isolating the naturally selected and evolved variants of those AAVs that are proven to be efficient gene transfer vehicles in certain tissue targets such as AAV1 to muscle, AAV5 to lung, AAV6 for muscle, AAV9 for liver, heart and brain by crossing the blood-brainbarrier. The research in this area will not only lead to more novel vector candidates for different applications but also shed light on how AAV evolves in nature.

2. AAV2-based gene therapeutics has been extensively studied in different clinical applications, demonstrating some impressive safety profiles. However, as those more efficient novel primate AAV-derived vectors move into the clinical evaluation stage, it is critically important for us to study interactions of those vectors with endogenous AAVs, host genome and host innate defense systems and potential consequences of such interactions. This is the second area of research interest in the lab.

4. To date, more than 600 different species of micro RNAs have been discovered. However, the functionality of those miRNAs in mammals and their possible associations with human diseases remain largely unknown. One attractive strategy to study their function in animal models is to take the advantage of tissue tropism and efficiency of AAV vector to overexpress either miRNAs or their antagonists in adult animals to disrupt miRNA homeostasis. To this end, our lab works on the design, optimization and delivery of expression cassettes for miRNA or their antagonist as well as analysis of biological consequences of their stable over expression by rAAV..

5. Canavan disease is a devastating genetic disease, resulting in fetal white matter spongy degeneration. Currently, there is no effective clinical intervention for the disease. Gene therapy represents a highly promising option for treating the disease. The major challenge for this approach is to efficiently target the entire white matter for gene replacement therapy. A recent study revealed that intravascularly delivered AAV9, one of the novel primate AAVs we previously isolated, can cross the blood-brain barrier and realize extensive gene transfer to both neurons and astrocytes in CNS. Our lab evaluates a panel of natural variants of AAV9 to identity the vector candidates that not only can efficiently cross the blood-brain barrier for CNS gene transfer but also are less immunogenic and toxic. The goal is to combine novel vector platform with miRNA-mediated gene expression regulation for development of effective and safe gene therapeutics for Canavan disease.